DAMPs and PAMPs and immune system dysregulation

[Snow Leopard]

I noticed that Griffith University (Australia) had the following as a research project:

Prof. Sonya Marshall-Gradisnik
Phone: *removed*
Email: *removed*
Chronic Fatigue Syndrome (CFS) is a heterogeneous and multifactorial disorder that affects many individuals worldwide. There is currently no definitive diagnosis for CFS and an exact mechanism to explain the manifestation of this disorder remains to be determined. However, CFS is known to be associated with alterations in immune function including NK activity, neutrophil phagocytosis and cytokine distribution. The National Centre for Neuroimmunology and Emerging Diseases (NCNED) is a leading research centre for CFS/ME research. The primary focus of this research centre is to determine markers for CFS/ME diagnosis by examining molecular and cellular parameters. It is well known that the immune system in CFS/ME is severely compromised
Project 1. An Investigation of the Inflammasome in Chronic Fatigue Syndrome
Infection and insults to tissues induces inflammation. The immune system has receptors that recognise pathogen associated molecular patterns (PAMPS) released by pathogens and damaged associated molecular patterns (DAMPS) released by the host in response to the pathogen invasion. These receptors form complexes that induce caspases and pro-inflammatory cytokines. The recognition of reduced cytotoxic activity, impaired neutrophil function and altered production of cytokines in CFS/ME are suggestive of persistent pathogen infiltration possibly causing increases in inflammation. This project examines these PAMPS and DAMPS and their receptors in CFS/ME to determine their role in the impaired immune profiles observed in these patients

See:
http://en.wikipedia.org/wiki/DAMPs
http://en.wikipedia.org/wiki/Pathogen-associated_molecular_pattern

Along with this interesting hypotheses such as:
"Dangers Within: DAMP Responses to Damage and Cell Death in Kidney Disease" (open access)
http://jasn.asnjournals.org/content/22/3/416.full

DAMPs have been suggested as possible risk factors leading to (regulatory) loss of control of antibody producing cells. There is also the possiblity of DAMPs themselves causing antibody independent feedback loops resulting in immune system dysregulation.

I am a little skepetical, at least with regards to the role in CFS, but it seems like an interesting avenue.

I am wondering what @Jonathan Edwards and others think about this?

 

[Jonathan Edwards]

It all sounds very vague to me. Genetic polymorphisms in DAMP or PAMP receptors might alter thresholds for an inflammatory mechanism in ME/CFS but the weight of evidence is that there isn't much inflammation in ME. Polymorphisms might also change the threshold for an innate signal that could get tied up in an autoimmune loop - rather in the way that the DR4 Class II polymorphism facilitates anti-citrulline antibodies. But it does not say if they are looking at genetics. Otherwise I am not sure where you would put DAMP/PAMP in a pathogenesis cascade other than somewhere downstream just as mediators - and I am not clear quite what they would be mediating.

The statement on severe immune compromise in ME seems a bit free-floating.

 

[Snow Leopard]

Otherwise I am not sure where you would put DAMP/PAMP in a pathogenesis cascade other than somewhere downstream just as mediators - and I am not clear quite what they would be mediating.

My personal hypothesis is that impaired cellular stress responses are involved in ME/CFS, in the absence of a strong inflammatory immune response (for reasons I will explain soon, hopefully). so I would actually predict a blunted DAMP/PAMP response. If autoimmunity is involved, then I would indeed expect it to be elsewhere.

 

[Marco]

I've no idea what they're proposing. If anywhere I'd be looking at a possible role for primed microglia over-reacting to a wide range of DAMPS/PAMPS which I believe is what Jared Younger is proposing with respect to his findings correlating leptin levels with fatigue. Leptin as far as I know hasn't as yet been identified as a DAMP/alarmin but its an emerging field and other signals relevant to 'energetics' such as ATP have.

 

[Jonathan Edwards]

Yes, the problem for me would be why DAMP and PAMP responses suddenly malfunctioned when the disease started. I don't get a feel for any specific dynamics here.